Fluorine in pharmaceuticals

Among the lessons which I learnt in graduate school was another important one: organic fluorine rarely forms hydrogen bonds. The layman's explanation for this phenomenon is that F holds tightly on to its electrons and does not share them.

However, there are enough number of examples among protein-ligand interactions, although much fewer than the other ones, to warrant attention to the role of F in drugs. The review in the latest issue of Science does exactly that. (DOI: 10.1126/science.1131943)

Some of the salient points I got from this and other reviews:

1. F as bioisostere: As is known, because of its similar size, F can be a good bioisostere for O, and C-F bonds can stand in for C-O bonds. The review mentions C-CF3 as substitute for C-O, and vinyl C=C-F as substitute for peptide bonds. The introduction of F can considerably alter conformational preferences. The review mentions the interesting case of O-CH3 vs O-CF3 bonded to an aromatic ring. In the former, the group is in the plane of the ring because of pi-orbital conjugation with the ring, whereas in the latter, O-antibonding C-F orbital conjugation destroys this preference and swings the group orthogonal to the ring.

2. F as acidity promoter: It is well-known that F increases the acidity of amines. In some cases, one can decrease the pKa to below 7, so that the amines will not be protonated at physiological pH. This can have the consequence both of improving permeability by increasing the neutral form of the amine, and radically changing the binding mode. A remarkable example is of a series of thrombin inhibitors, where the pKa could be decreased from 10 to <2 by introducing well-positioned Fs. I have already talked about the exceptional case of 3-F piperidines.

3. F as lipophilicity enhancer: Another important property of increasing the logD value. The review also mentions cases where the logD actually falls. F's lipophilicity has been famously incorporated into Teflon®, and hexafluoroisopropanol and hexafluoroacetone are often used to enhance alpha-helical content of peptides on the basis of this property. Balaram and Rajan have argued that these solvents actually "dry" the peptides ("Teflon coated peptides")

4. F as H-bonder: A unique property of this chap. I always remember a review by Dunitz in which he statistically examined a large number of CSD entries and found an exceedingly small number of cases where organic F could be a bonafide H-bond acceptor. However, there are also cases, where F in ligands shows close proximity to C-H, N-H, and most interestingly, C=O bonds where F interacts with the carbonyl carbon. This is in contrast to the recently investigated "halogen bonds" where Br and Cl seem to interact with carbonyl oxygen in proteins.

Clearly, F's behaviour in enhancing protein-drug interactions is valuable. And it remains as interesting and enigmatic as ever. An always colorful beast.

8 comments:

Probably the most important role of fluorine in pharmaceuticals is to block metabolism. To do this effectively it needs to be small and relatively insignificant (so as not to compromise potency). A CF3 group is like a halogen that you can put next to heteroaromatioc nitrogen. I've not looked at the interactions with carbonyl carbon stuff recently. How much does one of these interactions actually contribute to binding? You probably saw my comment on kinasepro about fluorine next to anions (e.g. CF2PO3--) 'acquiring' some of the anionic character of the adjacent group. I think you'll see this sort of thing in PTP1B complexes of difluorophosphonates. Not exactly pharmaceutical I know.

GMC: I would think that the interaction would not contribute more than a kcal or two. The hydrophobic gain might be more important. Blocking metabolism is I guess important for preventing things like oxidation of double bonds. The effects on things like CF2PO3 are interesting.

The recent science review on fluorine in pharmaceuticals is a real nice review. In the case of -OCF3 vs –OCH3, the –OCF3 not only changes the conformation but also reduces the electron density of phenyl group, because the –OCF3 is a stronger electro-withdrawing group than –CF3 in many cases. Just recently, -SF5 has been used as an alternative to –CF3 in pharmaceuticals. Some patents just claimed –SF5 containing compounds as novel potential therapeutics and around 10-20 compounds are in preclinical stages. Compare –OCF3 and –SF5, -SF5 might bring more effects on target molecules due to its unique electro- and steric properties. However, we do not know the toxicity of –SF5.

-CO-NF- compounds have been widely used as a new kind of electrophilic fluorination agent since early 1990. I never heard it has been used as bioactive compds, because –CI-NF- compds are moisture sensitive and highly chemical reactive.

This stuff about SF5 is interesting. Not really related, byt for some reason it reminds me that SF6 apparently is so safe that it can be breathed. Do you have a reference for SF5 in medchems?About the fluorination, I am not really a synthetist, but couldn't you use some electrophilic F reagent like Selectfluor or something?

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“Ashutosh (Ash) Jogalekar is a scientist and science writer based in the San Francisco Bay Area. He has been blogging at the “Curious Wavefunction” blog for more than ten years, and in this capacity has written for several organizations including Nature, Scientific American and the Lindau Meeting of Nobel Laureates. His professional areas of interest include medicinal and computational chemistry. His literary interests specifically lie in the history and philosophy of science.”
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